Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.

Abstract

The intricate process of dendritic arborization is essential for forming functional neural circuits, and many of the underlying molecular and cellular mechanisms have been uncovered. However, how they are linked to regulate dendritic arborization in neurons remains further exploration. Through genetic screening, we identify the splicing factor Sf3b1 as functioning cell-autonomously in neuronal dendrite growth and maintenance. Our transcriptomic analysis links Sf3b1-regulated alternative splicing to modulation of metabolic pathways, and we assess altered splicing patterns for several mitochondria-related genes. Importantly, Sf3b1 knockdown in neurons results in dramatic mitochondrial fragmentation and specific reductions in mitochondrial counts and ATP levels in dendrites, revealing a pivotal role for Sf3b1 in modulating the energy supply necessary for dendritic arborization. Additionally, a genetic rescue experiment uncovered mitophagy-modulating molecules that effectively restored the mitochondrial health and dendritic arborization of Sf3b1-depeted neurons. Our study establishes a previously unrecognized connection between RNA splicing and mitochondrial demand in differentiating neurons, providing insights into bioenergetic requirements for dendritic growth and maintenance.